Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect. There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition, of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose (2-DG) in suppressing carcinogenesis in experimental animal models. The clinical applications of resveratrol and 2-DG, however, are hampered by their weak potencies. Our studies have identified thiazolidinediones (TZDs) as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of silent information regulator (Sirt)1 expression, activation of the intracellular fuel sensor AMP-activated protein kinase (AMPK), and endoplasmic reticulum (ER) stress, the interplay among which culminated in autophagic and apoptotic cell death. These results provided a molecular basis to conduct lead optimization of TZDs, which netted OSU-CG12 (CG12) exhibiting an-order-of-magnitude higher potency than resveratrol in restricting tumor metabolism by blocking glucose uptake. Thus, this competing renewal proposal is aimed at testing the hypothesis that the unique ability of CG12 to target energy metabolism has translational potential in prostate cancer prevention. Three Specific Aims are proposed. Aim 1 is to conduct the mechanistic characterization of the mode of action of CG12 in mediating energy restriction. We will identify the mechanism underlying the suppressive effects of CG12 on glucose utilization, examine the role of p53 in CG12-induced apoptotic and autophagic cell death, and investigate the mechanism underlying CG12-mediated suppression of HIF-1a, which plays a critical role in regulating cell metabolism through the metabolic switch to glycolysis and the development of resistance to 2-DG. Aim 2 is to continue the lead optimization of CG12 to develop potent ERMAs. Aim 3 is to assess the in vivo efficacy of an optimized ERMA to block prostate tumorigenesis in the TRAMP and PTEN-deficient mouse models. Together, the proposed studies will effectively translate our novel finding that TZDs uniquely target tumor metabolism to preclinical development of a novel class of ERMAs with significant chemopreventive potential.